Organelle Cross Talk and Membrane Dynamics

Our cells are divided into distinct membrane-bound compartments some of which form pathways that transport materials into and out of cells. These membrane trafficking pathways control key cellular processes including nutrient uptake, clearance of activated growth factor receptors, and the secretion of hormones and neurotransmitters. However our understanding of membrane trafficking systems remains incomplete. Our research integrates cell biology, biochemistry, and system-wide approaches to better understand how membrane trafficking and cell signalling pathways allow cells to respond to cues in their environment, such as growth factors, nutrients, and stress. Our long-term goal is to develop new therapeutics for the treatment of diseases caused by membrane trafficking defects.

Cells and tissues communicate with one another through the release of hormones and neurotransmitters that are recognized by signaling receptors on target cells. As such, cell-cell communication is tightly coupled to membrane trafficking pathways that control the secretion of signaling factors and the targeting of cell-surface receptors. Our group is investigating the structural requirements and physiological roles for membrane lipid dynamics in cell signaling and membrane trafficking pathways. This work is revealing novel roles for ‘intracellular synapses’ between the between the endoplasmic reticulum (ER) and plasma membrane (PM). We are elucidating how the assembly and disassembly of ER-PM contacts are regulated and how distinct ER-PM contacts modulate phosphoinositide (PI) kinase regulatory networks. PI kinase signalling networks control several key cellular processes including cell growth and survival, cell polarity, and membrane trafficking pathways. Consequently, defects in PI kinase regulatory networks have been implicated in numerous human diseases including cancer, diabetes, and neurodegenerative disorders. It is vital that we understand how cells maintain and use these essential signalling molecules. We are currently undertaking multidisciplinary approaches–including cell biological assays, high-resolution microscopy, proteomics, lipidomics, and biochemical approaches–to make new discoveries into the regulation of PI kinase signaling networks by ER-PM cross talk. We expect that these investigations will reveal new insights into the complex regulatory processes that ensure the temporal and spatial specificity of membrane trafficking systems, including regulated exocytosis and endocytosis necessary for pulsatile insulin secretion and neurotransmission.
Moreover, we have found that ER-PM cross talk is essential for normal ER morphology and function. Loss of ER-PM contacts causes dramatic changes in ER organization and architecture, resulting in activation of ER stress response pathways. Recent findings have placed ER stress as a key component of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). We are currently elucidating the vital roles for PM-ER contacts in ER membrane homeostasis, as well as the essential cellular pathways induced in response to membrane stress.